The present invention relates to a process for producing 5-fluorouracil. More particularly, it relates to a novel process for producing 5-fluorouracil from a starting material of orotic acid in advantageous manners by a combination of a fluorination and a decarboxylation.
It has been known that 5-fluorouracil is useful as an antitumour agent or in an intermediate for various antitumour agents.
Various syntheses of 5-fluorouracil have been proposed. For example, the synthesis of 5-fluorouracil by using ethylmonofluoroacetate as a starting material has been disclosed in U.S. Pat. No. 2,802,005 and Japanese Patent Publication No. 9578/1961. This process has disadvantages of the use of the toxic starting material and many steps and low yield of the object product, in an industrial production.
It has been also proposed to produce 5-fluorouracil by a fluorination of uracil with a fluorinating agent such as fluorine gas and trifluoromethyl hypofluorite in Japanese Patent Publication No. 25476/1975, U.S. Pat. No. 3,682,917, Japanese Unexamined Patent Publication Nos. 9127/1972 and 149,287/1976.
In accordance with the studies, the following disadvantages have been found in the process for producing 5-fluorouracil by a fluorination of uracil with a fluorinating agent.
The solubility of uracil to water is similar to that of 5-fluorouracil whereby it is not easy to isolate the unreacted uracil by a recrystallization, etc. Accordingly, in the conventional process, the fluorination should be completed to control the residue of the unreacted uracil. However, the fluorination is a severe exothermic reaction whereby a decomposition or a modification of the object product may be caused if the complete fluorination is performed. That is, high conversion leads to low selectivity to the object product. If the conversion is lowered for high selectivity, the trouble of recovery and recycle of the unreacted uracil is caused because of said difficulty of the isolation of the object product.